Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • See Evidence submitted by expert panel for details.

Variant: NM_000546.5(TP53):c.814G>A (p.Val272Met)

CA000427

185814 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome 1
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: f3006a48-5b31-4ef1-8f3d-575a86c78f1b
Approved on: 2022-03-18
Published on: 2022-03-18

HGVS expressions

NM_000546.5:c.814G>A
NM_000546.5(TP53):c.814G>A (p.Val272Met)
NC_000017.11:g.7673806C>T
CM000679.2:g.7673806C>T
NC_000017.10:g.7577124C>T
CM000679.1:g.7577124C>T
NC_000017.9:g.7517849C>T
NG_017013.2:g.18745G>A
ENST00000269305.9:c.814G>A
ENST00000269305.8:c.814G>A
ENST00000359597.8:n.814G>A
ENST00000413465.6:n.782+375G>A
ENST00000420246.6:c.814G>A
ENST00000445888.6:c.814G>A
ENST00000455263.6:c.814G>A
ENST00000504290.5:c.418G>A
ENST00000504937.5:c.418G>A
ENST00000509690.5:c.418G>A
ENST00000510385.5:c.418G>A
ENST00000610292.4:c.697G>A
ENST00000610538.4:c.697G>A
ENST00000610623.4:c.337G>A
ENST00000615910.4:n.781G>A
ENST00000617185.4:c.814G>A
ENST00000618944.4:c.337G>A
ENST00000619186.4:c.337G>A
ENST00000619485.4:c.697G>A
ENST00000620739.4:c.697G>A
ENST00000622645.4:c.697G>A
ENST00000635293.1:c.697G>A
NM_001126112.2:c.814G>A
NM_001126113.2:c.814G>A
NM_001126114.2:c.814G>A
NM_001126115.1:c.418G>A
NM_001126116.1:c.418G>A
NM_001126117.1:c.418G>A
NM_001126118.1:c.697G>A
NM_001276695.1:c.697G>A
NM_001276696.1:c.697G>A
NM_001276697.1:c.337G>A
NM_001276698.1:c.337G>A
NM_001276699.1:c.337G>A
NM_001276760.1:c.697G>A
NM_001276761.1:c.697G>A
NM_001276695.2:c.697G>A
NM_001276696.2:c.697G>A
NM_001276697.2:c.337G>A
NM_001276698.2:c.337G>A
NM_001276699.2:c.337G>A
NM_001276760.2:c.697G>A
NM_001276761.2:c.697G>A
NM_000546.6:c.814G>A
NM_001126112.3:c.814G>A
NM_001126113.3:c.814G>A
NM_001126114.3:c.814G>A
NM_001126115.2:c.418G>A
NM_001126116.2:c.418G>A
NM_001126117.2:c.418G>A
NM_001126118.2:c.697G>A
NM_001276695.3:c.697G>A
NM_001276696.3:c.697G>A
NM_001276697.3:c.337G>A
NM_001276698.3:c.337G>A
NM_001276699.3:c.337G>A
NM_001276760.3:c.697G>A
NM_001276761.3:c.697G>A
NM_000546.6(TP53):c.814G>A (p.Val272Met)
More

Pathogenic

Met criteria codes 4
PM1 PM6_Strong PS4_Moderate PS3
Not Met criteria codes 9
BA1 PM5 PM2 BS2 BS3 BS1 BP4 PS1 PP3

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
TP53 VCEP
This variant has >10 observations as a somatic hotspot variant in tumors (PM1; cancerhotspots.org v(2)). Transactivation assays show a low functioning allele according to Kato, et al. and there is evidence of a dominant negative effect and loss of function according to Giacomelli, et al. (PS3; PMID: 12826609, 30224644). This variant has been reported in 4 probands meeting Chompret criteria (PS4_Moderate; PMID: 25584008, 23175693, IARC, NIH). There are de novo observations in 2 probands with childhood rhabdomyosarcoma, osteosarcoma, without parental confirmation (PM6_Strong; PMID: IARC, NIH). In summary, TP53 c.814G>A (p.Val272Met) meets criteria to be classified as pathogenic for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PM1, PS3, PS4_Moderate, PM6_Strong.
Met criteria codes
PM1
Yes, 34/66 samples on cancerhotspots.com
PM6_Strong
2 de novo points (Strong) for highest-weighted cancers in probands (NIH cohort and IARC)
PS4_Moderate
2 phenotype points; 1 case of Chompret from NIH cohort, 1 case of Chompret from IARC, 2 cases of Chompret from literature (PMID: 25584008, 23175693)
PS3
Kato non-functional; Kotler LOF; Giacomelli DNE and LOF
Not Met criteria codes
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
V272A (ClinVar: 565884, 1x VUS); V272E (ClinVar: 376673, LP somatic only); V272G (ClinVar: 233323, 1x VUS); V272L (1) (ClinVar: 574679, 1x VUS); V272L (2) (ClinVar: 12358, 1x LP); None evaluated by VCEP
PM2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS2
Absent from FLOSSIES. Internal cases in 60+ women are at low VAF and suspicious for CHIP
BS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
1 allele in European non-Finnish in gnomAD (non-cancer) (AF = 0.000009756)
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP3
aGVGD = C15; BayesDel = 0.5009
Curation History
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.
¤ Powered by BCM's Genboree.